Abstract
The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (Foxp3) expression has not been found. Here, we report that Foxp3 blocked the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shut down basal Ca2+ oscillation in Tregs, which reduced m-calpain activities that are needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency rendered the CD4+ T cell pool immune suppressive and caused it to behave in the same manner as Foxp3+ Tregs in viral infection, asthma, hypersensitivity, colitis, and tumor development. In the absence of Foxp3, Ryr2-deficient CD4+ T cells rescued the systemic autoimmunity associated with scurfy mice. Therefore, Foxp3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.
Authors
Xiaobo Wang, Shuang Geng, Junchen Meng, Ning Kang, Xinyi Liu, Yanni Xu, Huiyun Lyu, Ying Xu, Xun Xu, Xinrong Song, Bin Zhang, Xin Wang, Nuerdida Nuerbulati, Ze Zhang, Di Zhai, Xin Mao, Ruya Sun, Xiaoting Wang, Ruiwu Wang, Jie Guo, S.R. Wayne Chen, Xuyu Zhou, Tie Xia, Hai Qi, Xiaoyu Hu, Yan Shi
Figure 5
RyR2 deficiency–mediated suppression operates in the absence of specific antigen.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)